This application for renewal of a Hepatitis C Cooperative Research Center (HCV CRC) focuses on the multicellular mechanisms employed by HCV to evade or suppress the immune response. Three highly inter-related projects from PIs who have worked closely together in a productive manner will characterize diverse components of innate and adaptive immunity that influence whether spontaneous resolution or viral persistence occurs. The proposal fulfills several of the stated aims of this RFA, including but not limited to: 1. Identify effectors of HCV-induced innate immune signaling (project 1, aim 3; project 3); describe their mechanisms in HCV control (project 1/aim 1, aim 3); explain how HCV inhibits innate immune pathways (project 1/aim 1; project 3/aim3). 2. Determine the mechanisms of the adaptive immunity in clearance of HCV infection and their functional collapse leading to virus persistence (project 1/aims 1 and 2; project 2/ alms 1, 2, and 3. Clarify how the innate and adaptive immune responses are integrated to effect clearance of HCV infection (project 1/ aim 1 .project 3/ aim 3). The overarching objective of this Center application is to understand the multi-cellular processes involved in mediating recovery from HCV infection, and conversely, why these processes often fail and lead to viral persistence, and furthermore, identify targets to rescue cells from immune exhaustion and failure. As evident from our track record, the individual projects benefit significantly from their participation in this HCV CRC since each investigator brings unique expertise and resources from substantially different yet complementary areas of research. These include clinical hepatology, cellular and molecular immunology, virology, cell biology, and systems biology.